What makes UpToDate so powerful?

  • over 10000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Patient Print
0 Find synonyms

Find synonyms Find exact match

Clinical manifestations and diagnosis of Ehlers-Danlos syndromes
UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
Clinical manifestations and diagnosis of Ehlers-Danlos syndromes
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jul 08, 2016.

INTRODUCTION — Ehlers-Danlos syndrome (EDS) is the term used for a group of relatively rare genetic disorders of connective tissue which are characterized by one or another of several features, including skin hyperextensibility, joint hypermobility, and tissue fragility. The overall frequency of the Ehlers-Danlos syndromes is 1 in 5000, with EDS hypermobility type being by far the most common and some types being quite rare. The disorders are distinguished from one another and can often be diagnosed based upon the family history and clinical criteria, including the degree and nature of involvement of skin, joints, skeleton, and vasculature [1]. The genetic basis for most types of EDS has been defined, other than for the hypermobility type (that is likely genetically heterogeneous), and genetic testing may be useful diagnostically for several of these disorders.

The relationship between EDS, hypermobility type, and joint hypermobility syndrome remains uncertain; some experts have suggested that EDS, hypermobility type, and joint hypermobility syndrome may be manifestations of the same disorder [2,3]. (See 'Hypermobility EDS' below and 'Differential diagnosis' below and "Joint hypermobility syndrome".)

The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS will be presented here. An overview of the management of the Ehlers-Danlos syndromes, the clinical manifestations and treatment of the benign hypermobility syndrome, and overviews of the principles of genetic counseling and testing are reviewed separately. (See "Overview of the management of Ehlers-Danlos syndromes" and "Joint hypermobility syndrome" and "Genetic testing".)

CLASSIFICATION — The Villefranche classification scheme for Ehlers-Danlos syndrome (EDS), which was adopted in 1998, defines six subtypes based upon clinical features, mode of inheritance, and biochemical and genetic findings [1]. This revised nomenclature replaced the prior approach of identifying the different forms by number (eg, EDS Type I) [4]. The clinical diagnoses are based upon a series of major and minor criteria, differing according to EDS type, but additional patients may have overlapping features of different types, and are not easily categorized [5]

The six major types of EDS (and their former nomenclature) are:

Classic (EDS types I and II) (see 'Classic EDS' below)

Hypermobility (EDS type III) (see 'Hypermobility EDS' below)

Vascular (EDS type IV) (see 'Vascular EDS' below)

Kyphoscoliosis (EDS type VI) (see 'Kyphoscoliosis EDS' below)

Arthrochalasia (EDS type VIIA and B) (see 'Arthrochalasia EDS' below)

Dermatosparaxis (EDS type VIIC) (see 'Dermatosparaxis EDS' below)

The hypermobility type is much more common than the other types, with classic and vascular type each being more common than the remainder. Other much less frequently seen forms include spondylocheirodysplasia EDS and musculocontractural EDS; additional rare variants of EDS have also been described [6].

GENETICS AND PATHOGENESIS — In most types of Ehlers-Danlos syndrome (EDS), the underlying pathophysiology involves inherited alterations in genes affecting the synthesis and processing of different forms of collagen, which are important in the structure of many tissues and organs, including the skin, tendons, ligaments, vasculature, skeleton, and eyes [5,6]. A variety of different mutations that may cause an EDS phenotype have been identified for each of the affected genes.

Some forms of EDS are inherited in an autosomal dominant pattern, including the classic and vascular types, arthrochalasia, and most patients with the hypermobility type of EDS, thus requiring a single inherited copy of the abnormal gene for expression of the disease. Spontaneous mutations subsequently associated with an autosomal dominant pattern of inheritance may also occur. In other individuals and some rare types of EDS (eg, kyphoscoliosis EDS) the gene is inherited in an autosomal recessive pattern, with an altered copy from each parent present in those affected clinically. (See "Basic principles of genetic disease".)

The frequency and nature of the genetic abnormalities differ for each type (table 1) [6]:

Classic EDS – Classic EDS (Mendelian Inheritance in Man [MIM] #130000 and #130010) is inherited as an autosomal dominant disorder [7,8]. Mutations are found within the collagen genes, COL5A1 and COL5A2, in about 90 percent of patients who are diagnosed clinically [9]. About 50 percent of the patients diagnosed with classic EDS appear to have a de novo mutation, and neither parent is affected [10]. Type V collagen molecules, encoded for by the genes in which the mutations reside, interact with type I collagen molecules during collagen fibrillogenesis. Type I collagen is an integral component of the connective tissue, forming skin, tendons, ligaments, bones, and the aorta [11].

Hypermobility EDS – In most patients with hypermobility EDS (MIM #130020), inheritance appears to be autosomal dominant, but the underlying genetic abnormality is unknown and unmapped [12]. There is a rare subtype of hypermobility EDS due to tenascin X deficiency (MIM #606408, resulting from a mutation in the TNXB gene), which appears to be inherited in an autosomal recessive fashion [13]. Heterozygosity for tenascin X deficiency can be associated with mild features of disease, including joint hypermobility [14].

Vascular EDS – Vascular EDS (MIM #130050) is an autosomal dominant condition that results from mutations in type III procollagen; 50 percent of cases appear due to de novo mutations [15]. Most of the mutations are in the COL3A1 gene, causing an altered procollagen, which results in a “dominant negative effect.” Since type III collagen consists of a homotrimer, an abnormality in half of the type III procollagen molecules will result in greater than half of the resultant type III collagen molecules being abnormal. Haploinsufficiency mutations that result in half of the normal production of type III procollagen are much rarer; individuals with this type of mutation may have a milder phenotype and may not be diagnosed unless genetic testing is performed because of an affected family member [16].

Kyphoscoliosis EDS – Kyphoscoliosis EDS (MIM #225400) is an autosomal recessive disorder due to mutations in PLOD1, which results in lysyl hydroxylase deficiency [17]. Lysyl hydroxylase is a collagen-modifying enzyme which forms cross-links between the collagen trimers, increasing the collagen strength.

Arthrochalasia EDS – Arthrochalasia is an autosomal dominant form of EDS (MIM #130060) that is caused by a loss of exon 6 in either COL1A1 (EDS VIIA) or COL1A2 (EDS VIIB) resulting in structural defects in type I collagen [18,19]. Exon 6 codes for the procollagen N-proteinase cleavage site, which enables the precursor procollagen of either the alpha-1 or alpha-2 chains of type I collagen to be modified into mature collagen. The result of mutations affecting this region is abnormal weak collagen.

Dermatosparaxis EDS – Dermatosparaxis is a rare form of EDS (MIM #225410) that is inherited in an autosomal recessive fashion. It is due to mutations in the ADAMTS2 gene, which result in deficiency of procollagen I N-terminal peptidase [20].

The genetic abnormalities in other rare forms of EDS have also been described. Among these are spondylocheirodysplasia EDS (MIM #612350), an autosomal recessive disorder due to mutation in the zinc transporter gene, SLC39A13; and musculocontractural EDS (MIM #601776), an autosomal recessive disorder caused by mutations in the CHST14 gene.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Overview — A variety of clinical features are seen in the different forms of Ehlers-Danlos syndrome (EDS), often resulting in skin hyperextensibility, joint hypermobility, and tissue fragility (see 'Joint hypermobility' below and 'Skin hyperextensibility' below). The particular manifestations in the skin, joints, and other tissues, including the vasculature, depend upon the specific type of EDS that is present. Some features characteristic of one type may not be seen in patients with a different form of EDS [6,21]. Consequently, the clinical diagnostic criteria for the different forms of EDS are distinct from one another. The utility of genetic testing for confirmation of the diagnosis also varies between types.

The diagnosis of EDS in one of its forms should be suspected when a patient presents with some combination of features seen in one or several of the types of EDS, including joint hypermobility, multiple joint dislocations, translucent skin, poor wound healing, easy bruising, and unusual scars. This diagnosis should also be considered in any young individual who experiences spontaneous rupture of an organ (eg, gut or uterus) or dissection of a major blood vessel. Referral to a clinical geneticist or other expert in EDS may be warranted for assistance in the diagnostic evaluation and management, particularly with respect to genetic testing. (See 'When to refer' below.)

Joint dislocations or subluxations are common in most forms of EDS, and joint pain and premature degenerative arthritis are often consequences of the disorder. Pes planus is common in all forms, and pectus excavatum and a high arched palate can also be present in all of the forms of EDS. Musculoskeletal pain is common in patients with joint hypermobility, and complex regional pain syndrome has been described as a rare complication with both the hypermobility and classic forms of EDS [22]. EDS patients, often appearing fit and healthy, may be misdiagnosed as hypochondriacal or pathologically depressed. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

Myopia can also be seen but is not specific, and retinal detachment can occur.

The clinical manifestations that characterize and distinguish each of the major forms of EDS and the approach to their diagnosis are each discussed separately. (See 'Classic EDS' below and 'Hypermobility EDS' below and 'Vascular EDS' below and 'Kyphoscoliosis EDS' below and 'Arthrochalasia EDS' below and 'Dermatosparaxis EDS' below.)

Definitions — The revised Villefranche classification for EDS included definitions of certain important features, including joint hypermobility and skin hyperextensibility [1].

Joint hypermobility — Joint hypermobility or laxity is the hallmark of most types of EDS. This can involve both proximal and distal joints or may be seen predominantly in distal joints (such as in vascular EDS). The assessment of the joints is done using the Beighton hypermobility scale, which is widely used in assessing hypermobility of peripheral joints and the spine, and is the scoring system most often used in epidemiological research [23,24]. One point is awarded for the ability to perform each of four maneuvers involving the extremities (bilaterally), and one point is awarded for having an unusually flexible spine. A score of at least five of the maximum total of nine points is used to define hypermobility in criteria for EDS [10,12]. The following maneuvers are performed:

Passive dorsiflexion of the fifth finger >90 degrees with forearm flat

Passive apposition of the thumb to the flexor aspect of the forearm

Hyperextension of elbow >10 degrees

Hyperextensibility of the knee >10 degrees

Flexion of waist with palms on the floor (and with the knees fully extended)

Skin hyperextensibility — Skin hyperextensibility is defined as the capacity to stretch the skin for 4 cm or more at a neutral site, such as the neck or ventral aspect of the forearm, until feeling resistance [8]. This is particularly true of the classic form. The hyperextensibility increases with age, but is present in children [9].

Mitral valve prolapse — Mitral valve prolapse has been reported as a feature of several forms of EDS. However, older estimates of the frequency of mitral valve prolapse should be interpreted with caution, as the criteria defining MVP have evolved, and studies prior to 1989 may have overestimated its prevalence. (See "Definition and diagnosis of mitral valve prolapse", section on 'Definition and classification'.)

Classic EDS

Clinical manifestations – Classic EDS, the severity of which can vary, is the term used collectively for the conditions formerly referred to as EDS gravis (EDS I) and EDS mitis (EDS II) [10]. EDS type I was characterized by more severe joint hypermobility and skin laxity than type II, but these two forms previously described as distinct types have subsequently been recognized as describing the range of findings along a continuum. The prevalence of classic EDS has been estimated at about 1 in 20,000, but some patients with milder forms may go unrecognized, and the frequency may be higher [7,8].

Both large and small joint hypermobility are typically seen, although the degree of hypermobility may decrease with age. In one study of 40 patients from 28 families, 8 of 40 (20 percent) of the patients lacked evidence of joint hypermobility [25]. Joint dislocations may be frequent and recurrent; joint subluxations of the shoulder, patella, and temporomandibular joints are often self-managed by the patient and may resolve spontaneously. Joint effusions sometimes occur, and patients can develop osteoarthritis. Skeletal abnormalities, including thoracolumbar scoliosis, may be seen in some patients.

The characteristic skin findings include velvety (“doughy”) hyperextensible and fragile skin, which extends easily and snaps back upon release, but may split easily with trauma; abnormal wound healing, with delayed healing and widened atrophic scars; and increased bruisability. The upper eyelid may be everted easily (Metenier sign) due to hyperextensibility of the eyelid. Other skin features include piezogenic papules (fat herniations through fascia on sides of feet), molluscoid pseudotumors (bluish-grey to violaceous, spongy 1 to 2 cm nodules over easily traumatized bony areas such as the shin, forearm, and Achilles tendon, which represent herniations of subcutaneous fat through atrophic dermal scars), and subcutaneous spheroids (several mm diameter, hard, calcified, subcutaneous nodules due to fat necrosis) [26].

Additional features include fatigue, development of hernias, cervical insufficiency, and uterine prolapse. Vascular complications are rare, but have been reported, and valvular heart disease is uncommon. The frequency of aortic root dilatation has been reported as 6 percent [27]. Mitral valve prolapse (MVP) has been observed in 6 percent of patients as well (see 'Mitral valve prolapse' above) [28]. Pulmonary complications, including spontaneous pneumothorax, are reported. Gastrointestinal and bladder diverticula may occur [21].

Diagnosis – The diagnosis is made clinically, based upon the family history and physical examination. It can be made in the presence of three major criteria along with any minor criterion [9]:

Major criteria: skin hyperextensibility, widened atrophic papyraceous (cigarette paper-like)_scars with poor wound healing, joint hypermobility.

Minor criteria: smooth velvety skin, molluscoid pseudotumors, subcutaneous spheroids, complications of joint hypermobility, muscle hypotonia, delayed development, hernias, anal prolapse, cervical insufficiency, and a positive family history.

Diagnostic testing: The diagnosis can be confirmed by DNA sequencing of COL5A1 and COL5A2. Patients who fulfill the clinical criteria should be referred to a clinical geneticist, who may order the testing for confirmation and for genetic counseling purposes.

Hypermobility EDS

Clinical manifestations – The major physical features of hypermobility EDS (EDS III) include large and small joint and spine hypermobility; frequent joint dislocations, often affecting a shoulder, the patella, or the temporomandibular joint; and chronic joint pain, which often develops, may resemble fibromyalgia, and can have an adverse impact on the quality of life [29]. Patients may also develop scoliosis and premature osteoarthritis. The frequency of the hypermobility form of EDS is unknown, although it is at least 1 in 5000 [12].

The skin is sometimes soft and smooth, but usually not to the degree seen in classic EDS, where it is typically described as velvety; only mild hyperextensibility is evident, if present. Wound healing is normal. Molluscum pseudotumors do not occur, unlike patients with classic EDS. Piezogenic papules may be seen. Keratosis pilaris/hyperkeratosis of the extensor surfaces and striae can occur [30]. Skin changes are generally modest compared with classic EDS, but small, postsurgical, wide, non-papyraceous scars can occur [30]

Other features and complications include delayed gastric emptying and irritable bowel syndrome. Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), which can be detected by tilt table testing, can occur [31,32]. Such patients may experience syncope, sleep disturbance including apnea, swelling and varicosities of legs, headache including “brain fog,” and poor proprioception [33]. Autonomic instability can also be associated with postural acrocyanosis after several minutes of standing in some patients [34]. One report has also suggested an association with occipitoatlantoaxial hypermobility and Chiari type I malformation [35]. Headaches are reported in about one-third of patients (including migraines, tension-type headaches, headache from cerebrospinal fluid leakage, headache from Chiari malformation, and cervicogenic headache (from cervical spine hypermobility) [36]. Resistance to local anesthetic drugs and opioids has been reported.

Mild aortic root dilatation can be seen in 12 percent of patients, and the frequency of mitral valve prolapse has been reported as 6 percent [28]. (See 'Mitral valve prolapse' above.)

Diagnosis – The diagnosis is made clinically. All three major criteria should be present:

Major criteria: skin involvement with hyperextensibility and/or smooth skin, NO wide scars or evidence of skin or tissue fragility, and generalized joint hypermobility (small and large joints).

Minor criteria: recurrent joint dislocations, chronic joint/limb pain (early onset, chronic), and positive family history.

Caveats: Joint hypermobility is more common in females and in young children (those under five years of age). In addition, as patients get older joint hypermobility may lessen, especially with the development of arthritis and following surgical intervention. In this situation, the history of previous joint laxity is noted.

Diagnostic testing: Genetic testing for most patients with this form is not available. Tenascin X DNA testing is available outside of the United States, but the frequency of this abnormality in patients with hypermobility EDS is not known; it is likely rare.

The relationship between EDS, hypermobility type, and joint hypermobility syndrome remains uncertain. The molecular genetic bases for these disorders are unknown; thus molecular evidence to clarify their relationship is lacking. (See 'Differential diagnosis' below and "Joint hypermobility syndrome".)

Vascular EDS

Clinical manifestations – Vascular EDS (EDS IV) is potentially life-threatening, and differs from the classic and hypermobility forms most dramatically in the increased risk for these patients of spontaneous vascular or visceral rupture and the absence of large joint hyperextensibility. Small (more distal) joints, however, may exhibit mild hypermobility. The prevalence of the vascular form of EDS is not well studied, but estimates based upon available data suggest a frequency of at least 1 in 100,000, accounting for about 4 percent of all EDS cases [15].

Arterial rupture may involve the iliac, splenic, or renal arteries; or the aorta. Preexisting aneurysms are rarely detected prior to a rupture, as the aneurysms are typically pseudoaneurysms. Complications in affected individuals also include significant risk for spontaneous rupture of internal organs (such as the intestine and gravid uterus) and muscles. Maternal mortality during pregnancy is about 12 percent, although delivery is often uneventful [15].

The skin is thin and may appear translucent with a prominent venous pattern (especially on the chest and abdomen), atrophic scars, increased bruisability, and varicosities. Wound dehiscence may occur postoperatively. However, the skin is only mildly hyperextensible. Minor trauma leads to extensive bruising.

Skeletal abnormalities include acrogeria, characterized by a lack of subcutaneous fat in the distal extremities; and a particular facial appearance with prominent eyes, thin face and nose, and lobeless ears. Gingival recession is common. Short stature may be seen but is not typical. Clubfoot has been reported in 12 percent of neonates with vascular EDS, and 3 percent have congenital hip dislocations [15].

Eighty percent of individuals experience a major vascular event or rupture of an internal organ by age 40 years. There is a shortened lifespan with a median age of death of 48 years [15].

Diagnosis – The following criteria have been proposed, with two major criteria having a high specificity and two minor criteria suggesting need for further testing [37]:

Major criteria: arterial rupture, intestinal rupture, uterine rupture, positive family history.

Minor criteria: thin translucent skin, characteristic facial appearance (thin face, large appearing eyes, thin lips, thin nose), acrogeria, hypermobility of small joints, tendon and muscle rupture, talipes equinovarus, early onset varicosities, pneumothorax, gingival recession.

Diagnostic testing: Sequence and deletion/duplication testing of the COL3A1 gene has a high sensitivity. Analysis of type III procollagen from fibroblasts may also be performed.

Kyphoscoliosis EDS

Clinical manifestations – Kyphoscoliosis EDS (EDS VI) typically presents in newborns with muscle hypotonia associated with joint laxity, often leading to an initial evaluation by a neurologist [38]. Kyphoscoliosis may be present at birth, and develops in nearly all patients. Progressive kyphoscoliosis can result in respiratory complications and often requires surgery. Patients with this form exhibit joint hypermobility and can experience recurrent joint dislocations. Osteoporosis can be seen, and clubfoot deformity may occur in about 30 percent. The skin is hyperextensible and typically velvety, pale, and translucent, with poor wound healing. About 50 percent may have atrophic scarring and 50 percent may have severe bruising [39]. Vascular fragility may be present and spontaneous vascular rupture may occur.

Ocular involvement may occur, unlike in most other forms of EDS, including the presence of scleral fragility, risk of rupture of ocular globe, keratoconus, retinal detachment, and glaucoma.

The frequency is estimated at 1 in 100,000 [17].

Diagnosis – The diagnosis is based upon the presence of at least three major features [39]:

Major features: early onset severe congenital hypotonia; progressive scoliosis, which is present at birth or occurs during the first year of life; generalized joint laxity; and scleral fragility.

Minor features: widened atrophic scars, marfanoid habitus, rupture of medium-sized arteries, and mild to moderate delay of attainment of gross motor milestones.

Diagnostic testing: The diagnosis can be made by measurement in urine of the ratio of lysyl pyridinoline to hydroxylysylpyridinoline. The mean value of this ratio in kyphoscoliosis EDS is about 6.0, compared with 0.2 in normal individuals. Activity of the enzyme in fibroblasts (with enzyme activity being below 25 percent of normal) and DNA sequence analysis of the PLOD1 gene for the enzyme procollagen-lysine, 2-oxoglutarate 5 dioxygenase-1, can also be performed.

Arthrochalasia EDS

Clinical manifestations – Arthrochalasia EDS (EDS VIIA, VIIB) is characterized by hypermobility with recurrent subluxations, congenital hip dislocations, extremity contractures, thoracolumbar scoliosis, short stature (as a complication of the scoliosis), muscle hypotonia, and frequent fractures [18]. Complications include fractures and recurrent dislocations, which can prevent weightbearing. The skin is fragile and hyperelastic, and may have a doughy texture. Its frequency is unknown, although this form is extremely rare.

Diagnosis – The diagnosis is made clinically based upon the presence of severe generalized joint hypermobility with recurrent dislocations, congenital hip dislocation, and a combination of the other clinical features noted.

Laboratory testing: The diagnosis can be confirmed by COL1A1 and COL1A2 DNA sequencing with analysis of exon 6.

Dermatosparaxis EDS

Clinical manifestations – Features of dermatosparaxis EDS (EDS VIIC) include severe skin fragility, sagging redundant skin, and large hernias [40,41]. Blue sclerae can be present. The major complications are related to the severe skin fragility. The skin can have a velvety “doughy” texture. Its frequency is unknown.

Diagnosis – The diagnosis is made by sequencing of the ADAMTS2 gene.

Other rare forms of EDS — Several other very rare forms of EDS have been described [42-44]; their precise frequency is uncertain. Two of these are:

Spondylocheirodysplasia EDS – Clinical features of this form include short stature; blue sclera; delayed eruption of teeth and hypodontia; joint laxity and a particular pattern of skeletal findings (platyspondyly, osteopenia, widened metaphyses, flattened epiphyses, small ilia, short broad femoral necks and short metacarpals and phalanges); velvety, hyperextensible, thin skin with prominent veins; and delayed wound healing with atrophic scars [42]. Laboratory testing in these patients demonstrates that the ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine is elevated compared with normal (about 0.9 in patients versus 0.2 in normals), but the degree of elevation is not as high as seen with kyphoscoliosis EDS (see 'Kyphoscoliosis EDS' above). DNA sequencing of the SLC39A13 gene is available.

Musculocontractural EDS – Clinical features of this form include specific craniofacial features (broad forehead, small mouth, and micrognathia in infancy; protruding jaw in adolescence; low-set prominent rotated ears, blue sclerae, short nose, thin upper lip, and long philtrum), thumb and finger contractures, club feet, severe kyphoscoliosis, hypotonia, hyperextensible thin skin with easy bruising, atrophic scars, joint laxity, and organ fragility [43,44]. DNA sequencing of the CHST14 gene can be performed.

DIFFERENTIAL DIAGNOSIS — In addition to the other types of Ehlers-Danlos syndrome (EDS), the differential diagnosis includes the joint hypermobility syndrome and other disorders of connective tissue. Hypermobility EDS may be difficult to distinguish from joint hypermobility syndrome, which is a much more common condition characterized by musculoskeletal pain and generalized joint hypermobility. Joint hypermobility syndrome is considered by many experts in rheumatology and in clinical genetics to be indistinguishable from, if not identical to, the most common variant of EDS, EDS-hypermobility type, but the precise relationship between EDS-hypermobility type and joint hypermobility syndrome remains uncertain and molecular genetic confirmation is needed [2,45,46] (see "Joint hypermobility syndrome") Several connective tissue disorders share some features with EDS, but clinically distinct features are typically also present [46]. These conditions include those described below.

Marfan Syndrome — Marfan syndrome, like EDS, is typically characterized by joint laxity. It is inherited in an autosomal dominant pattern, due to mutations in the FBN1 gene. Joint hypermobility, scoliosis, and mild aortic dilatation can be seen in patients with Marfan syndrome, as in EDS; but the disproportionate tall stature, dislocation of the lens, pectus carinatum, and progressive aortic dilatation distinguish Marfan syndrome from the different types of EDS. In addition, the skin findings seen in the classic form of EDS are not typical for Marfan syndrome. Features characteristic of Marfan syndrome include overgrowth of long bones, dislocation of the lens, retinal detachment, pectus excavatum and/or carinatum, scoliosis, heart valve dysfunction, and aortic dilatation with a propensity to aortic rupture. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

Cutis laxa — Cutis laxa is characterized by loose, redundant skin which only slowly returns from distension [47]. Heart valve regurgitation and other vascular involvement can occur. Hernias and emphysema are common. There are several different forms, inherited in both autosomal recessive and dominant fashion. While the skin may be easily stretched in patients with EDS as well, in EDS it is hyperextensible and returns quickly from distention, differentiating the skin changes in EDS from those of cutis laxa.

Loeys-Dietz Syndrome — Loeys-Dietz syndrome involves aortic and other arterial aneurysm and dissection, but also includes generalized arterial tortuosity, hypertelorism (widely-spaced eyes), cleft palate, or bifid uvula. Some patients with Loeys-Dietz syndrome may have translucent skin and atrophic scars very similar to the changes seen in patients with vascular EDS; but the cleft palate, bifid uvula, and arterial tortuosity seen in Loeys-Dietz syndrome are not typically found in patients with EDS. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Loeys-Dietz syndrome'.)

Osteogenesis imperfecta — Osteogenesis imperfecta is a group of disorders whose main features are fragile osteopenic bones with recurrent fractures. In some forms, there can be blue sclerae, hearing loss, and progressive skeletal deformity. Joint laxity is common, but the hallmark features of osteogenesis imperfecta, which are the recurrent fractures and osteopenia, are rarely seen in EDS. Inheritance is autosomal dominant or recessive, depending upon the specific type. (See "Osteogenesis imperfecta: Clinical features and diagnosis".)

Larsen syndrome — Larsen syndrome consists of dislocations of large joints (hips, knees, and elbows), specific craniofacial features (flat midface, depressed nasal bridge, and cleft palate), short stature, and clubfoot [48]. There are both autosomal dominant and autosomal recessive forms. While joint dislocations are seen in both EDS and Larsen syndrome, the specific craniofacial features seen in Larsen syndrome are not seen in patients with EDS.

Stickler syndrome — Stickler syndrome is characterized by specific craniofacial features (flattened midface, cleft palate, micrognathia), high myopia with risk for retinal detachment, hearing loss, and spondyloarthropathy. Affected individuals may have a marfanoid habitus and joint laxity. Joint dislocations are not typical. It is autosomal dominantly inherited with several different genes being responsible. Patients with Stickler syndrome can have joint laxity, but they have other features which are not typical in the various EDS syndromes, such as hearing loss, very high myopia, and the characteristic craniofacial features and cleft palate seen in this other syndrome. (See "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'.)

Arterial tortuosity syndrome — Arterial tortuosity syndrome is an autosomal recessive condition characterized by generalized tortuosity of large- and medium-size arteries, with increased risk of aneurysms, dissections, and ischemic stroke. There can be pulmonary artery and aortic stenosis. The skin can be soft and hyperextensible, suggesting EDS, but there is normal wound healing and no increased bruisability. The face can be long with a long philtrum and a high arched palate. Hernias and pectoral anomalies may be present, and keratoconus, joint laxity, arachnodactyly, and joint contractures can be seen. Arterial tortuosity syndrome is distinguished from Loeys Dietz syndrome based upon the absence of uvular abnormalities or micrognathia, and by molecular genetic testing for abnormalities of the SLC2A10 gene [49].

WHEN TO REFER — Patients suspected of having Ehlers-Danlos syndrome (EDS) based upon their clinical presentation and family history should be referred for consultation with an expert in clinical genetics or the care of patients with EDS for confirmation of the diagnosis and the institution of multidisciplinary management and follow-up care. The evaluation should include a general physical examination, with particular attention to an evaluation of ophthalmologic status; examination of skin texture, translucency, extensibility and integrity; assessment of range of motion of the joints, including determination of the Beighton score (see 'Joint hypermobility' above); and evaluation of other skeletal findings. The geneticist or other EDS expert can help to determine which, if any, genetic testing may be needed to assist in making or confirming the diagnosis.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Ehlers-Danlos syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Ehlers-Danlos syndrome (EDS) is the term used for a group of relatively rare disorders of connective tissue, due to inherited alterations in genes affecting the synthesis and processing of different forms of collagen. These conditions are characterized by one or another of several features, including skin hyperextensibility, joint hypermobility, and tissue fragility. The disorders are classified into six major types, which can be distinguished from one another clinically, and genetic testing may be useful diagnostically for several of these disorders (table 1). Additional rare variants of EDS have also been described. (See 'Classification' above and 'Overview' above and 'Genetics and pathogenesis' above.)

EDS should be suspected when a patient presents with some combination of characteristic features, including joint hypermobility, multiple joint dislocations, translucent skin, poor wound healing, easy bruising, hyperextensible skin, and unusual scars; and in any individual who experiences spontaneous rupture of an organ or dissection of a blood vessel. Joint dislocations or subluxations are common in most forms of EDS, and joint pain and premature degenerative arthritis are often consequences of the disorder. Other common features include pes planus, pectus excavatum, and a high arched palate. Musculoskeletal pain is common in patients with joint hypermobility. (See 'Overview' above and 'Definitions' above.)

Classic EDS (EDS types I and II), the severity of which can vary, is characterized by skin hyperextensibility; widened atrophic scars; and both large and small joint hypermobility, which may decrease with age. Frequent and recurrent joint dislocations are common, osteoarthritis can develop, and scoliosis may be seen. The characteristic skin findings include velvety (“doughy”) hyperextensible and fragile skin, which extends easily and snaps back upon release, but may split easily with trauma; abnormal wound healing, with delayed healing and widened atrophic scars; and increased bruisability. Additional features include fatigue, development of hernias, cervical insufficiency and uterine prolapse, and rare vascular complications. Valvular heart disease is uncommon. The diagnosis can be confirmed by DNA sequencing of COL5A1 and COL5A2. (See 'Classic EDS' above.)

The major features of hypermobility EDS (EDS type III) include large and small joint and spine hypermobility, which may lessen with age, and frequent joint dislocations. Chronic joint pain, which may resemble fibromyalgia, is common. Patients may also develop scoliosis and premature osteoarthritis. Skin is sometimes soft and smooth, but usually not to the degree seen in classic EDS, and only mild hyperextensibility is evident, if present. Wound healing is normal, without atrophic scars or evidence of skin or tissue fragility. Other features and complications include delayed gastric emptying, irritable bowel syndrome, and autonomic dysfunction. Aortic root dilatation and mitral valve prolapse are uncommon but can occur. Genetic testing for most patients with this form is not available, but a small subset of patients may have abnormalities in tenascin X DNA. (See 'Hypermobility EDS' above.)

Vascular EDS (EDS IV) is potentially life-threatening, and is characterized by increased risk of spontaneous vascular or visceral rupture and the absence of large joint hyperextensibility. Arterial rupture may involve the iliac, splenic, or renal arteries; or the aorta. Preexisting aneurysms are rarely detected prior to a rupture, as the aneurysms are typically pseudoaneurysms. There is significant risk for spontaneous rupture of internal organs (such as the intestine and gravid uterus) and muscles, and increased risk of maternal mortality during pregnancy. The skin is thin and may appear translucent with a prominent venous pattern, atrophic scars, increased bruisability, and varicosities, but is only mildly hyperextensible. Skeletal abnormalities may also be present. Substantial morbidity and mortality occurs by the fifth decade of life. The diagnosis can usually be confirmed by sequence and deletion/duplication testing of the COL3A1 gene. (See 'Vascular EDS' above.)

Additional forms of EDS include kyphoscoliotic (EDS type VI), in which ocular involvement may be present, in addition to muscle hypotonia and joint laxity present at birth, kyphoscoliosis detected during infancy and other skeletal changes, and abnormal skin; arthrochalasia (EDS type VIIA and B), which is characterized by hypermobility with recurrent subluxations, congenital hip dislocations, extremity contractures, thoracolumbar scoliosis, short stature, muscle hypotonia, and frequent fractures; dermatosparaxis (EDS type VIIC), with severe skin fragility, sagging redundant skin, and large hernias; and other rare forms. (See 'Kyphoscoliosis EDS' above and 'Arthrochalasia EDS' above and 'Dermatosparaxis EDS' above and 'Other rare forms of EDS' above.)

The differential diagnosis of each form of EDS includes the other EDS types and other connective tissue disorders with shared features, including Marfan syndrome, osteogenesis imperfecta, and several other uncommon or rare disorders that can usually be distinguished clinically from EDS. Whether hypermobility EDS and joint hypermobility syndrome represent distinct entities or the same condition remains uncertain. (See 'Differential diagnosis' above.)

Patients suspected of having EDS based upon their clinical presentation and family history should be referred for consultation with an expert in clinical genetics or the care of patients with EDS for confirmation of the diagnosis and the institution of multidisciplinary management and follow-up care. The geneticist or other EDS expert can help to determine which, if any, genetic testing may be needed to assist in making or confirming the diagnosis. (See 'Differential diagnosis' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. Beighton P, De Paepe A, Steinmann B, et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 1998; 77:31.
  2. Tinkle BT, Bird HA, Grahame R, et al. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A 2009; 149A:2368.
  3. Hermanns-Lê T, Reginster MA, Piérard-Franchimont C, et al. Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome. J Biomed Biotechnol 2012; 2012:878107.
  4. Beighton P, de Paepe A, Danks D, et al. International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am J Med Genet 1988; 29:581.
  5. Callewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol 2008; 22:165.
  6. De Paepe A, Malfait F. The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet 2012; 82:1.
  7. Malfait F, Wenstrup RJ, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med 2010; 12:597.
  8. Malfait F, Wenstrup R, De Paepe A. Ehlers-Danlos Syndrome, Classic Type. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1244/?report=printable (Accessed on May 18, 2013).
  9. Symoens S, Syx D, Malfait F, et al. Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 2012; 33:1485.
  10. Ehlers-Danlos Syndrome, Classic Type. Malfait F, Wenstrup R, De Paepe A. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2007 May 29 [updated 2011 Aug 18]. http://www.ncbi.nlm.nih.gov/pubmed/20301422 (Accessed on May 18, 2013).
  11. Byers PH. Disorders of collagen biosynthesis and structure. In: The Metabolic and Molecular Basis of Inherited Disease, 2nd, Scriver, Beaudet, Sly, Valle (Eds), Churchill Livingstone, Edinburgh 2001. p.1065.
  12. Levy HP. Ehlers-Danlos Syndrome, Hypermobility Type. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1279/?report=printable (Accessed on May 18, 2013).
  13. Schalkwijk J, Zweers MC, Steijlen PM, et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 2001; 345:1167.
  14. Zweers MC, Bristow J, Steijlen PM, et al. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet 2003; 73:214.
  15. Pepin MG, Byers PH. Ehlers-Danlos Syndrome Type IV. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1494/?report=printable (Accessed on May 18, 2013).
  16. Leistritz DF, Pepin MG, Schwarze U, Byers PH. COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet Med 2011; 13:717.
  17. Yeowell hn, Steinmann B. Ehlers-Danlos syndrome, kyphoscoliotic form. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. http://www.ncbi.nlm.nih.gov/books/NBK1462/?report=printable (Accessed on May 18, 2013).
  18. Giunta C, Superti-Furga A, Spranger S, et al. Ehlers-Danlos syndrome type VII: clinical features and molecular defects. J Bone Joint Surg Am 1999; 81:225.
  19. Byers PH, Duvic M, Atkinson M, et al. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet 1997; 72:94.
  20. Colige A, Sieron AL, Li SW, et al. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am J Hum Genet 1999; 65:308.
  21. Steinmann B, Royce PM, Superti-Furga A. The Ehlers-Danlos syndrome. In: Connective Tissue and its Heritable Disorders: Molecular, Genetic and Medical Aspects, 2nd, Royce PM, Steinmann B (Eds), Wiley Liss, New York 2002. p.431.
  22. Stoler JM, Oaklander AL. Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain 2006; 123:204.
  23. Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis 1973; 32:413.
  24. Juul-Kristensen B, Røgind H, Jensen DV, Remvig L. Inter-examiner reproducibility of tests and criteria for generalized joint hypermobility and benign joint hypermobility syndrome. Rheumatology (Oxford) 2007; 46:1835.
  25. Ritelli M, Dordoni C, Venturini M, et al. Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis 2013; 8:58.
  26. Inamadar AC, Palit A. Cutaneous signs in heritable disorders of the connective tissue. Indian J Dermatol Venereol Leprol 2004; 70:253.
  27. Wenstrup RJ, Meyer RA, Lyle JS, et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 2002; 4:112.
  28. Atzinger CL, Meyer RA, Khoury PR, et al. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. J Pediatr 2011; 158:826.
  29. Rombaut L, Malfait F, Cools A, et al. Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type. Disabil Rehabil 2010; 32:1339.
  30. Castori M, Dordoni C, Morlino S, et al. Spectrum of mucocutaneous manifestations in 277 patients with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet C Semin Med Genet 2015; 169C:43.
  31. Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med 2003; 115:33.
  32. Mathias CJ, Low DA, Iodice V, et al. Postural tachycardia syndrome--current experience and concepts. Nat Rev Neurol 2011; 8:22.
  33. Castori M. Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatol 2012; 2012:751768.
  34. Rowe PC, Barron DF, Calkins H, et al. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr 1999; 135:494.
  35. Milhorat TH, Bolognese PA, Nishikawa M, et al. Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue. J Neurosurg Spine 2007; 7:601.
  36. Castori M, Morlino S, Ghibellini G, et al. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain. Am J Med Genet C Semin Med Genet 2015; 169C:84.
  37. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342:673.
  38. Wenstrup RJ, Murad S, Pinnell SR. Ehlers-Danlos syndrome type VI: clinical manifestations of collagen lysyl hydroxylase deficiency. J Pediatr 1989; 115:405.
  39. Ehlers-Danlos Syndrome, Kyphoscoliotic Form. Yeowell HN, Steinmann B. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013 February 2, 2000; Last Update: January 24, 2013. http://www.ncbi.nlm.nih.gov/books/NBK1462/?report=printable (Accessed on June 13, 2013).
  40. Reardon W, Winter RM, Smith LT, et al. The natural history of human dermatosparaxis (Ehlers-Danlos syndrome type VIIC). Clin Dysmorphol 1995; 4:1.
  41. Malfait F, De Coster P, Hausser I, et al. The natural history, including orofacial features of three patients with Ehlers-Danlos syndrome, dermatosparaxis type (EDS type VIIC). Am J Med Genet A 2004; 131:18.
  42. Giunta C, Elçioglu NH, Albrecht B, et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 2008; 82:1290.
  43. Kosho T, Miyake N, Hatamochi A, et al. A new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. Am J Med Genet A 2010; 152A:1333.
  44. Malfait F, Syx D, Vlummens P, et al. Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat 2010; 31:1233.
  45. Castori M, Dordoni C, Valiante M, et al. Nosology and inheritance pattern(s) of joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type: a study of intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet A 2014; 164A:3010.
  46. Colombi M, Dordoni C, Chiarelli N, Ritelli M. Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type compared to other heritable connective tissue disorders. Am J Med Genet C Semin Med Genet 2015; 169C:6.
  47. Berk DR, Bentley DD, Bayliss SJ, et al. Cutis laxa: a review. J Am Acad Dermatol 2012; 66:842.e1.
  48. Bicknell LS, Farrington-Rock C, Shafeghati Y, et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet 2007; 44:89.
  49. Callewaert B, De Paepe A, Coucke P. Arterial tortuosity syndrome. In: GeneReviews [Internet], Pagon RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2014.
Topic 14920 Version 10.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.